Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Abstract

The transcriptional events that control T cell tolerance are still poorly understood. To investigate why tolerant T cells fail to produce interleukin (IL)-2, we analyzed the regulation of NFκB-mediated transcription in CD4+ T cells after tolerance induction in vivo. We demonstrate that a predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells correlated with repression of NFκB-driven transcription. Impaired translocation of the p65 subunit in tolerant T cells was a result from reduced activation of IκB kinase and poor phosphorylation and degradation of cytosolic IκBs. Moreover, tolerant T cells expressed high amounts of the p50 protein. However, the increased expression of p50 could not be explained by activation-induced de novo synthesis of the precursor p105, which was constitutively expressed in tolerant T cells. We also demonstrate the exclusive induction of the IκB protein B cell lymphoma 3 (Bcl-3) in tolerant T cells as well as its specific binding to the NFκB site. These results suggest that the cellular ratio of NFκB dimers, and thus the repression of NFκB activity and IL-2 production, are regulated at several levels in tolerant CD4+ T cells in vivo.